Epidemiological evidence demonstrates that obesity is rising exponentially to pandemic levels in the USA. The failure of current pharmacological approaches to treat obesity strongly indicates that new therapeutic strategies are required. New strategies require new knowledge. We recently identified a peptide named TLQP-21 which is encoded by the VGF gene. TLQP-21 binds the G-protein coupled receptor Complement 3a receptor1 (C3aR1), potentiates ?-adrenergic receptors (?AR)-induced lipolysis and, reduces fat mass in obese mice. TLQP-21 also improves diabetes and has a very safe cardiovascular profile. Much remains to be established on it molecular mechanism of action. Similarly, the role of C3aR1 is well established in immunity but its functional role in adipocytes and obesity is poorly understood. We propose a project in which the Central Hypothesis will be tested that TLQP-21 opposes obesity by enhancing lipolysis with a mechanism requiring priming by cAMP and mediated by increased intracellular calcium concentration. The Specific Aim (SA)1 will determine the role of cAMP on priming TLQP-21-induced activation of C3aR1 in adipocytes and the role of increased [Ca2+]i on its pro-lipolytic effect. The SA2 will investigate the physiologicl consequence of introducing an inactive TLQP-21 mutant on the development of obesity in mice and the behavior of the peptide in a C3aR1 ko mouse. Finally, SA3 will focus on the pro-lipolytic effect of TLQP-21 in human adipocytes. The impact of successful achievement of the aims of this project will be significant on the field. After the failure of sympathomimetic drugs and other pro-lipolytic agents to cure obesity, current therapeutic approaches primarily target feeding or nutrient absorption through the gastro-enteric tract. These more recent approaches are not devoid of adverse effects. The mechanism of action of TLQP-21 has the potential to cure obesity by selectively and safely reducing the excessive adipose fat mass.